Cellular glutathione peroxidase-1 (GPX1) is the first identified selenium-dependent protein and a major intracellular antioxidant enzyme in mammals. While both selenium and antioxidant enzymes are thought to protect against diabetes, we have found a spontaneous development of type 2 diabetes-like phenotypes in GPX1 overexpressing (OE) mice. Because a novel 16 kDa pancreatic islet protein Reg2 was diminished in these mice, we hypothesize that the OE metabolic enigma is mainly caused by the GPX1 overproduction-mediated decrease of islet Reg2. Strikingly, administration of exogenous Reg2 protein to OE mice rescued their phenotypes. Therefore, we plan to use this unique animal model and purified Reg2 protein to conduct 8 major experiments for 3 specific aims. First, we will elucidate the mechanism by which GPX1 inhibits islet Reg2 gene transcription via modulating intracellular reactive oxygen species, selenium, and target proteins. Second, we will treat whole animals, isolated islets, and primary hepatocytes of both OE and wild- type mice with exogenous Reg2 protein to study its metabolic role, biochemical pathway, and signal transduction in rescuing the OE phenotypes. Lastly, we will search for a Reg2 receptor to connect the endocrine-like, global effects of exogenous Reg2 to specific intracellular biochemical reactions. Our proposal bears numerous conceptual and experimental innovations. Linking GPX1 overproduction to type 2 diabetes-like phenotypes for the first time creates a new field of selenium biology. Discovering regulatory mechanisms of Reg2 expression by GPX1 will bridge two unrelated fields, and expand the enzyme function beyond antioxidation. Elucidating mechanisms for the dramatic Reg2 rescue of the OE phenotypes will unveil a novel endocrine-like regulator of beta cell growth, insulin physiology, and lipogenesis, and lead to a powerful drug innovation to combat metabolic syndrome. Our research has tremendous health significance. A number of major human studies have recently shown alarming pro-diabetic, hyperglycemic, and hyperlipidemic effects of selenium supplements. Because GPX1 is the most abundant selenium-containing protein in the body, the type 2 diabetic-like OE mice offer us an ideal experimental model to tackle this urgent public health problem for the first time. Our finding will help elaborate the etiological mechanism and potential risk of selenium supplements in potentiating type 2 diabetes and metabolic syndrome that afflict 10 to 25% of the US population. PUBLIC HEALTH RELEVANCE: Major human studies have recently shown alarming risks of selenium supplements in potentiating type 2 diabetes and elevating blood glucose and lipid. As the most abundant selenium-containing protein in the body, glutathione peroxidase-1(GPX1) is widely considered to be a major antioxidant enzyme. Contrary to this perception, we have observed a spontaneous development of type 2 diabetes-like phenotypes in mice over-producing GPX1. Because a novel pancreatic protein Reg2 is diminished in these mice, we hypothesize that the decrease of Reg2 causes this metabolic enigma. Most striking, administration of exogenous Reg2 protein to these mice rescued their phenotypes. Thus, we propose to find out: 1) how GPX1 overproduction diminishes pancreatic islet Reg2; and 2) how exogenous Reg2 rescues the type 2 diabetes-like phenotypes. Our finding will help address the serious concern over the pro-diabetic risk of Se supplements, and will lead to a powerful innovation to treat type 2 diabetes and metabolic syndrome.